Abstract

Obsessive-compulsive disorder (OCD) is an anxiety-spectrum disorder characterized by persistent intrusive thoughts (obsessions) and repetitive actions (compulsions). Dysfunction of cortico-striato-thalamo-cortical circuitry is implicated in OCD, although the underlying pathogenic mechanisms are unknown. SAP90/PSD95-associated protein 3 (SAPAP3; also known as DLGAP3) is a postsynaptic scaffolding protein at excitatory synapses that is highly expressed in the striatum. Here we show that mice with genetic deletion of Sapap3 exhibit increased anxiety and compulsive grooming behaviour leading to facial hair loss and skin lesions; both behaviours are alleviated by a selective serotonin reuptake inhibitor. Electrophysiological, structural and biochemical studies of Sapap3-mutant mice reveal defects in cortico-striatal synapses. Furthermore, lentiviral-mediated selective expression of Sapap3 in the striatum rescues the synaptic and behavioural defects of Sapap3-mutant mice. These findings demonstrate a critical role for SAPAP3 at cortico-striatal synapses and emphasize the importance of cortico-striatal circuitry in OCD-like behaviours.

a, SAPAP3-/- mice have facial and neck skin lesions (arrows). b, c, SAPAP3-/- mice (KO) showed more grooming bouts (b) and spent more time in self-grooming (c) than wildtype mice (WT) at all times examined. d, Pre-lesion and post-lesion groups of SAPAP3-/- mice showed similar degrees of increased grooming. e,f, In the open field test, SAPAP3-/- mice spent less time in the center (e), whereas locomotion along the perimeter was comparable to wildtype controls (f). g-i, In the dark-light emergence test, SAPAP3-/- mice took longer to cross from the dark to the brightly lit chamber (g) and spent less time in the brightly lit chamber (h), while total activity in both chambers was similar (i). j-l, In the elevated zero maze, SAPAP3-/- mice took longer to cross into the open areas (j) and spent less time in these areas than wildtype controls (k), while total activity in both open and closed areas was similar (l). *p < 0.05, **p < 0.01, ***p < 0.001, repeated measures ANOVA for b-e and two-tailed t-test for f-l; all data are presented as means ± SEM from 8-9 mice per genotype, Cohen’s kappa for intra-observer agreement exceeded 0.92.

a, b, The levels of PSD95, PSD93 and Shank in striatal PSD fractions are not affected in SAPAP3-/- mice. The levels of NR1 and NR2B subunits are increased, whereas that of NR2A is decreased. β-actin and β-tubulin were used as loading controls. *p < 0.05, two-tailed t test. c, d, Electron micrographs show the presence of synaptic vesicles (arrowheads), postsynaptic densities (arrows) and dendritic spines (stars). e, The length of the PSD is not significantly different in wildtype and SAPAP3-/- mice. f, g, The thickness of the dense layer (f) of the PSD in SAPAP3-/- mice, but not the light layer (g), is reduced. p< 0.001, two-tailed t test; n=94 for wildtype and n=92 for SAPAP3-/- mice.